Haplotype analysis suggests that the two predominant mutations in Japanese patients with holocarboxylase synthetase deficiency are founder mutations

Abstract

Holocarboxylase synthetase (HCS) deficiency is a rare autosomal recessive disorder of biotin metabolism. Including three new Japanese patients we diagnosed in this study, ten Japanese families have, so far, been accumulated. In these families, the mutations 237Leu Ͼ Pro (seven alleles) and 1067delG (five alleles) were predominant; 508Arg Ͼ Trp and 550Val Ͼ Met mutations were identified in three families in the heterozygous form and in one patient in the homozygous form, respectively. To determine the origin of these mutations, we identified new polymorphic microsatellite markers in the HCS gene and analyzed the haplotypes of the patients. All the 237Leu Ͼ Pro and the 1067delG alleles were associated with haplotype 2-2. This finding is consistent with the notion that these mutations are founder mutations in the Japanese population. Three Japanese 508Arg Ͼ Trp alleles were associated with several haplotypes, including 2-3 and 1-4. The haplotype of a Taiwanese patient homozygous for the 508Arg Ͼ Trp mutation was 2-3/2-3. The haplotype of one Japanese patient homozygous for the 550Val Ͼ Met mutation was 1-4/1-4, whereas that of a Jewish patient with the same homozygous mutation was 2-3/2-3. Both mutations were associated with at least two haplotypes and were found in several ethnic groups. The changes 508Arg Ͼ Trp and 550Val Ͼ Met occurred at CpG dinucleotide. The data suggest that these two mutations represent a mutational hot-spot.

Holocarboxylase synthetase is an obligate participant in biotin-mediated regulation of its own expression and of biotin-dependent carboxylases mRNA levels in human cells

“…MCD-MK cells are homozygous for the mutation R508W, which is a strikingly biotin-responsive mutation in vitro (16) and is a frequent mutation detected in patients with biotin-responsive MCD (16,31,32). Incubation of biotin-starved normal and mutant cells with biotin showed that 10-to 100-fold higher biotin concentration was required by the mutant cells to restore HCS mRNA to similar levels.…”

Holocarboxylase synthetase deficiency: novel clinical and molecular findings

“…For the polymorphic markers in the HLCS gene in the Thai population, the number of CAAA and ATTC repeats ranged from 7 to 9 and 7 to 10, respectively, compared to 6 to 8 and 10 to 15 in the Japanese population (5). While the Japanese study revealed that two most common mutations, p.L237P and c.1067delG, were founder mutations, our data indicating that the most common mutation in the Thai population, p.R508W, was associated with at least three haplotypes, suggesting that it was rather a recurrent mutation.…”

“…As the c.1522C>T mutation was present in six out of eight alleles in our four patients, it was interesting to investigate whether it was a founder mutation in our Thai population. Two microsatellite markers, CAAA and ATTC, in HLCS introns 8 and 9 were used, as described by Yang et al (2000) (5). Fifty unaffected Thai individuals were examined for both markers by PCR and sequencing (Table 4).…”

“…Tetra‐nucleotide repeats, CAAA and ATTC in introns 8 and 9, respectively, were amplified as described by Yang et al (5). Primer pairs and PCR conditions were shown in Table 2.…”

Mutations in the holocarboxylase synthetase geneHLCS

“…The mutations L237P and 780delG are predominant only in Japanese patients [Aoki et al, 1995;Sakamoto et al, 1998;Yang et al, 2000Yang et al, , 2001. We investigated the haplotype of these two mutations and found that both mutant alleles were exclusively associated with haplotype 2-2.…”